Neramexane and salts thereof are valuable agents for the continuous therapy of patients suffering from diseases and conditions such as tinnitus, Alzheimer's dementia and neuropathic pain.
WO 99/01416 discloses the preparation of neramexane, neramexane hydrochloride or intermediate products starting from isophorone.
A further reaction scheme for the preparation of neramexane and neramexane hydrochloride also starting from isophorone is known from Danysz et al (“Amino-alkyl-cyclohexanes as a novel class of uncompetitive NMDA receptor antagonist”, Current Pharmaceutical Design, 2002, 8, 835-843). FIG. 1 of said publication discloses the following reaction sequences:

Another route for the preparation of neramexane and neramexane hydrochloride starting from isophorone is disclosed by Jirgensons et. al. in European J. Med. Chem. 35 (2000), 555-565 (Synthesis and structure-affinity relationships of 1,3,5-alkylsubstituted cyclohexylamines binding at NMDA receptor PCP site).
The addition salt of neramexane with methane sulfonic acid (the mesylate) is also known to be a potent drug for the above mentioned diseases (WO 2007/062815).
WO 99/01416 suggests to prepare the mesylate from the amino compound by acid addition according to conventional procedure, or neutralizing the hydrochloride resulting in the free base, and then re-acidifying the free base with methane sulfonic acid.
Schweizer (Erstellung eines Präformulierungskonzeptes für mittelständische Pharmaunternehmen unter besonderer Berücksichtigung des physikalisch-chemischen Eigenschaften neuer Arzneistoffe, dargestellt am Beispiel der NMDA-Antagonisten MRZ 2/579 and MRZ 2/576, Dissertation, Johann-Wolfgang-Goethe-University in Frankfurt/Main, 2001) suggests a variety of solvents, in which neramexane mesylate may be re-crystallized. Suitable solvents are ethyl acetate, acetone, dichloromethane, water, diethyl ether, 1,4-dioxane, ethanol 70%, ethanol 96%, isopropanol, and toluene. Re-crystallization from acetone and dichloromethane may result in solvates. The solvent may be removed at elevated temperature leading to a destruction of the solvates.